| Objective: Platelet activation and aggregation play a major role in acute coronary syndromes (ACS) and in thrombotic complications during and following percutaneous coronary interventions (PCI). Anti-platelet therapy can dramatically reduce ischemic complications. Clopidogrel, a new type of thienopyridine derivative, inhibits platelet aggregation induced by adenosine diphosphate (ADP). Clopidogrel is a prodrug requiring several biotransformation steps,mmediated mainly by cytochrome P-450 isoenzymes (CYP), in order to generate an active metabolite that binds irreversibly to the platelet ADP receptor P2Y12. Several large clinical trials (CLASSICS,CURE,CAPRIE)have shown that clopidogrel effectively prevents thrombotic events in patients with atherosclerotic vascular disease. It has a favorable profile of side effects and exhibits faster anti-platelet activities. Current guidelines recommend dual anti-platelet therapy with a combination of aspirin and clopidogrel for patients who have ACS or undergo PCI. The pharmacodynamic response to clopidogrel varies widely from subject to subject, some individual had weak response to clopidogrel, while some subjects even have no response. This poor response to clopidogrel is associated with an increased risk of recurrent ischemic events. At present the incidence of non-response to clopidogrel is 5% ~40%.PCI treatment might cause the by-effect of elevation of cardiac biomarkers such as cTnI and CK-MB in certain patients, therefore, anti-platelet treatment is presenting to the patients in order to alleviate the damage caused by PCI operation. The purpose of the present study was to find out the individual variable response to clopidogrel by measuring the change of platelet aggregation before and after taking the drug in patients with coronary heart disease. To analyze the factors that influence the poor response to clopidogrel and whether this phenomenon can cause the cardiac biomarkers increase after PCI.Method: 147 patients who were administered clopidogrel (75mg QD) were enrolled between January 2008 and October 2008, including 103 males and 44 females, with a mean age of 58.95±10.54 years, in which 39 patients underwent elective percutaneous coronary interventions. Before clopidogrel administration blood samples were obtained through venipuncture so as to measure the baseline platelet aggregation. Platelet aggregation was assessed with a mobile four-channel impedance aggregometer (Chrono-Log Corporation), which allowed measurement of aggregation within half an hour after blood sampling, using ADP (10μmol/L), ADP (20μmol/L) as the agonist. In addition, 4 days after clopidogrel administration, specimens were obtained to measure the platelet aggregation once more. According to the value change of platelet aggregation prior to and 4 days after clopidogrel administration, patients were divided into clopidogrel resistance group and non-clopidogrel resistance group. For the patients undergoing PCI, blood samples were collected prior to and 24 hours after PCI treatment to testing the changing levels of cardiac biomarkers which include cTnI, CK-MB and MYO, in addition to measuring the platelet aggregation prior to and 4 days after clopidogrel. Continuous variables were expressed as the mean value±standard deviation (SD), categorical variables were summarized as percentages. Independent-samples t test was performed to determine the differences between mean values for continuous variables of baseline and concom itant characteristics between the two groups. Categorical variables were compared using chi-square test. The influence of clinical baseline factors, concomitant medication, the platelet aggregation induced by ADP (10μmol/L, 20μmol/L) was evaluated by stepwise logistic regression analysis. A P value of <0.05 was considered statistically significant.Result: Among the 147 patients, 36 (24.49%) patients had clopidogrel resistance. The baseline characteristics such as age, gender, recent smoking history, incidence of hypercholesterolemia, hypertension, diabetes mellitus were not significantly different between the two groups (P>0.05). History of prior myocardium infarction (MI), the incidence of recent MI, history of stroke was more frequent in the clopidogrel resistance group, but there were not statistically significant when compared with the non-clopidogrel resistance.The use of concomitant drugs did not differ significantly between groups (P>0.05). Patients in the clopidogrel resistance group were more likely to have higher pre- and post-treament platelet aggregation induced by 20mol/LADP and 10mol/LADP (all P<0.05). Logistic stepwise regression analysis showed that the baseline platelet aggregation induced by 20mol/L ADP was independent predictor for developing clopidogrel resistance (P<0.05).According to the value change of platelet aggregation induced by 20mol/LADP prior to and post-treatment of clopidogrel, patients undergoing PCI were divided into clopidogrel resistance group and non-clopidogrel resistance group. Before the PCI, cTnI were normal (<1.00 ng/ml) in the clopidogrel resistance group and non-clopidogrel resistance group. The incidence of cTnI≥1.00 ng/ml was 70.00% in the clopidogrel resistance group and 34.48% in the non-clopidogrel resistance group after PCI, but there were no significant difference between the two groups (P>0.05). The incidence of cTnI≥3.00 ng/ml was 10.00% in the clopidogrel resistance group and 6.90% in the non-clopidogrel resistance group. There were also no significant difference between the two groups (P> 0.05).Before PCI, CK-MB were normal (<5.00 ng/ml) in the clopidogrel resistance group and the non-clopidogrel resistance group. The incidence of CK-MB≥5.00 ng/ml was 80.00% in the clopidogrel resistance group and 44.81% in the non-clopidogrel resistance group after PCI, but there were no significant difference between the two groups (P>0.05). None of patients has cTnI≥15.00 ng/ml in the clopidogrel resistance group and 6.90% non-clopidogrel resistance patients have cTnI≥15.00 ng/ml. There were no significant difference between the two groups (P<0.05).Before PCI, MYO were normal (<70.00 ng/ml) in the clopidogrel resistance group and in the non-clopidogrel resistance group. The incidence of MYO≥70.00 ng/ml was 10.00% in the group. None of patients has MYO≥70.00 ng/ml in the non-clopidogrel resistance group.Conclusion: There were some factors could cause clopidogrel resistance. The best important risk factors were the baseline platelet activation. Patients with higher pretreatment platelet aggregation induced by 20μmol/LADP had weak response to clopidogrel. That is, despite intensified anti-platelet therapy, they may also develop thrombotic events. Due to the small sample sizes of the study, whether the patients who were considered to be poor response to clopidogrel have higher risks during the treatment of PCI, should be further evaluated in a larger number of patients enrolled studies. Non-response patients undergoing PCI do not have increased stent thrombosis and myocardium injurycomplications compared with non-clopidogrel resist- ance patients. |
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